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Effect of normalization on statistical and biological interpretation of gene expression profiles.

ABSTRACT: An under-appreciated aspect of the genetic analysis of gene expression is the impact of post-probe level normalization on biological inference. Here we contrast nine different methods for normalization of an Illumina bead-array gene expression profiling dataset consisting of peripheral blood samples from 189 individual participants in the Center for Health Discovery and Well Being study in Atlanta, quantifying differences in the inference of global variance components and covariance of gene expression, as well as the detection of variants that affect transcript abundance (eSNPs). The normalization strategies, all relative to raw log2 measures, include simple mean centering, two modes of transcript-level linear adjustment for technical factors, and for differential immune cell counts, variance normalization by interquartile range and by quantile, fitting the first 16 Principal Components, and supervised normalization using the SNM procedure with adjustment for cell counts. Robustness of genetic associations as a consequence of Pearson and Spearman rank correlation is also reported for each method, and it is shown that the normalization strategy has a far greater impact than correlation method. We describe similarities among methods, discuss the impact on biological interpretation, and make recommendations regarding appropriate strategies.

SUBMITTER: Qin S

PROVIDER: S-EPMC3668151 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Effect of normalization on statistical and biological interpretation of gene expression profiles.

Qin Shaopu S Kim Jinhee J Arafat Dalia D Gibson Greg G

Frontiers in genetics 20130531

An under-appreciated aspect of the genetic analysis of gene expression is the impact of post-probe level normalization on biological inference. Here we contrast nine different methods for normalization of an Illumina bead-array gene expression profiling dataset consisting of peripheral blood samples from 189 individual participants in the Center for Health Discovery and Well Being study in Atlanta, quantifying differences in the inference of global variance components and covariance of gene expr ...[more]

PMID: 23755061

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Project description:MotivationNetwork diffusion and label propagation are fundamental tools in computational biology, with applications like gene-disease association, protein function prediction and module discovery. More recently, several publications have introduced a permutation analysis after the propagation process, due to concerns that network topology can bias diffusion scores. This opens the question of the statistical properties and the presence of bias of such diffusion processes in each of its applications. In this work, we characterized some common null models behind the permutation analysis and the statistical properties of the diffusion scores. We benchmarked seven diffusion scores on three case studies: synthetic signals on a yeast interactome, simulated differential gene expression on a protein-protein interaction network and prospective gene set prediction on another interaction network. For clarity, all the datasets were based on binary labels, but we also present theoretical results for quantitative labels.ResultsDiffusion scores starting from binary labels were affected by the label codification and exhibited a problem-dependent topological bias that could be removed by the statistical normalization. Parametric and non-parametric normalization addressed both points by being codification-independent and by equalizing the bias. We identified and quantified two sources of bias-mean value and variance-that yielded performance differences when normalizing the scores. We provided closed formulae for both and showed how the null covariance is related to the spectral properties of the graph. Despite none of the proposed scores systematically outperformed the others, normalization was preferred when the sought positive labels were not aligned with the bias. We conclude that the decision on bias removal should be problem and data-driven, i.e. based on a quantitative analysis of the bias and its relation to the positive entities.AvailabilityThe code is publicly available at https://github.com/b2slab/diffuBench and the data underlying this article are available at https://github.com/b2slab/retroData.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:Microarray and beadchip are two most efficient techniques for measuring gene expression and methylation data in bioinformatics. Biclustering deals with the simultaneous clustering of genes and samples. In this article, we propose a computational rule mining framework, StatBicRM (i.e., statistical biclustering-based rule mining) to identify special type of rules and potential biomarkers using integrated approaches of statistical and binary inclusion-maximal biclustering techniques from the biological datasets. At first, a novel statistical strategy has been utilized to eliminate the insignificant/low-significant/redundant genes in such way that significance level must satisfy the data distribution property (viz., either normal distribution or non-normal distribution). The data is then discretized and post-discretized, consecutively. Thereafter, the biclustering technique is applied to identify maximal frequent closed homogeneous itemsets. Corresponding special type of rules are then extracted from the selected itemsets. Our proposed rule mining method performs better than the other rule mining algorithms as it generates maximal frequent closed homogeneous itemsets instead of frequent itemsets. Thus, it saves elapsed time, and can work on big dataset. Pathway and Gene Ontology analyses are conducted on the genes of the evolved rules using David database. Frequency analysis of the genes appearing in the evolved rules is performed to determine potential biomarkers. Furthermore, we also classify the data to know how much the evolved rules are able to describe accurately the remaining test (unknown) data. Subsequently, we also compare the average classification accuracy, and other related factors with other rule-based classifiers. Statistical significance tests are also performed for verifying the statistical relevance of the comparative results. Here, each of the other rule mining methods or rule-based classifiers is also starting with the same post-discretized data-matrix. Finally, we have also included the integrated analysis of gene expression and methylation for determining epigenetic effect (viz., effect of methylation) on gene expression level.

Dataset Information

Effect of normalization on statistical and biological interpretation of gene expression profiles.

Publications

Effect of normalization on statistical and biological interpretation of gene expression profiles.

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